Human and mouse essentiality screens as a resource for disease gene discovery.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery

Composite Coatings Based on Recombinant Spidroins and Peptides with Motifs of the Extracellular Matrix Proteins Enhance Neuronal Differentiation of Neural Precursor Cells Derived from Human Induced Pluripotent Stem Cells

The production and transplantation of functionally active human neurons is a promising approach to cell therapy. Biocompatible and biodegradable matrices that effectively promote the growth and directed differentiation of neural precursor cells (NPCs) into the desired neuronal types are very important. The aim of this study was to evaluate the suitability of novel composite coatings (CCs) containing recombinant spidroins (RSs) rS1/9 and rS2/12 in combination with recombinant fused proteins (FP) carrying bioactive motifs (BAP) of the extracellular matrix (ECM) proteins for the growth of NPCs derived from human induced pluripotent stem cells (iPSC) and their differentiation into neurons. NPCs were produced by the directed differentiation of human iPSCs. The growth and differentiation of NPCs cultured on different CC variants were compared with a Matrigel (MG) coating using qPCR analysis, immunocytochemical staining, and ELISA. An investigation revealed that the use of CCs consisting of a mixture of two RSs and FPs with different peptide motifs of ECMs increased the efficiency of obtaining neurons differentiated from iPSCs compared to Matrigel. CC consisting of two RSs and FPs with Arg–Gly–Asp–Ser (RGDS) and heparin binding peptide (HBP) is the most effective for the support of NPCs and their neuronal differentiation

Transcription of <i>HOX</i> Genes Is Significantly Increased during Neuronal Differentiation of iPSCs Derived from Patients with Parkinson’s Disease

Parkinson’s disease (PD) is the most serious movement disorder, but the actual cause of this disease is still unknown. Induced pluripotent stem cell-derived neural cultures from PD patients carry the potential for experimental modeling of underlying molecular events. We analyzed the RNA-seq data of iPSC-derived neural precursor cells (NPCs) and terminally differentiated neurons (TDNs) from healthy donors (HD) and PD patients with mutations in PARK2 published previously. The high level of transcription of HOX family protein-coding genes and lncRNA transcribed from the HOX clusters was revealed in the neural cultures from PD patients, while in HD NPCs and TDNs, the majority of these genes were not expressed or slightly transcribed. The results of this analysis were generally confirmed by qPCR. The HOX paralogs in the 3′ clusters were activated more strongly than the genes of the 5′ cluster. The abnormal activation of the HOX gene program upon neuronal differentiation in the cells of PD patients raises the possibility that the abnormal expression of these key regulators of neuronal development impacts PD pathology. Further research is needed to investigate this hypothesis

Chronic Unpredictable Mild Stress Model of Depression: Possible Sources of Poor Reproducibility and Latent Variables

Major depressive disorder (MDD) is one of the most common mood disorders worldwide. A lack of understanding of the exact neurobiological mechanisms of depression complicates the search for new effective drugs. Animal models are an important tool in the search for new approaches to the treatment of this disorder. All animal models of depression have certain advantages and disadvantages. We often hear that the main drawback of the chronic unpredictable mild stress (CUMS) model of depression is its poor reproducibility, but rarely does anyone try to find the real causes and sources of such poor reproducibility. Analyzing the articles available in the PubMed database, we tried to identify the factors that may be the sources of the poor reproducibility of CUMS. Among such factors, there may be chronic sleep deprivation, painful stressors, social stress, the difference in sex and age of animals, different stress susceptibility of different animal strains, handling quality, habituation to stressful factors, various combinations of physical and psychological stressors in the CUMS protocol, the influence of olfactory and auditory stimuli on animals, as well as the possible influence of various other factors that are rarely taken into account by researchers. We assume that careful inspection of these factors will increase the reproducibility of the CUMS model between laboratories and allow to make the interpretation of the obtained results and their comparison between laboratories to be more adequate

Autonomic neuropathy in diabetes mellitus: Clinical manifestations, diagnosis and treatment

Autonomic neuropathy (AN) is a disabling and life-threatening complication of diabetes mellitus and a number of other diseases. The timely diagnosis of this condition and early initiation of its therapy make it possible to prolong life and to improve its quality. The quantitative autonomic testing procedure permits one not only to diagnose AN and to detect the degree of autonomic nerve fiber lesion, but also to trace a trend in autonomic disorders during treatment, i.e. to evaluate the efficiency of therapy for cardiovascular AN